Special Warning : אזהרת שימוש

4.4 Special warnings and precautions for use
Hypotension: rarely hypotension is observed in uncomplicated hypertensive patients.
Symptomatic hypotension is more likely to occur in hypertensive patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea, vomiting or haemodialysis. Volume and/or sodium depletion should be corrected before the administration of an ACE inhibitor and a lower starting dose should be considered.
Patients with heart failure are at higher risk of hypotension and a lower starting dose is recommended when initiating therapy with an ACE inhibitor. The magnitude of the decrease is greatest early in the course of treatment; this effect stabilises within a week or two, and generally returns to pre-treatment levels, without a decrease in therapeutic efficacy, within two months.
Caution should be used whenever the dose of captopril or diuretic is increased in patients with heart failure.
As with any antihypertensive agent, excessive blood pressure lowering in patients with ischaemic cardiovascular or cerebrovascular disease may increase the risk of myocardial infarction or stroke. If hypotension develops, the patient should be placed in a supine position. Volume repletion with intravenous normal saline may be required.
Infants, especially new-borns, may be more susceptible to the adverse haemodynamic effects of captopril. Excessive, prolonged and unpredictable decreases in blood pressure and associated complications, including oliguria and seizures have been reported.
Renovascular hypertension: there is an increased risk of hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with ACE inhibitors. Loss of renal function may occur with only mild changes in serum creatinine. In these patients, therapy should be initiated under close medical supervision with low doses, careful titration and monitoring of renal function.
Renal impairment: The incidence of adverse reactions to captopril is principally associated with renal function since the drug is excreted primarily by the kidney. In cases of renal impairment (creatinine clearance ≤ 40 ml/min), the initial dosage of captopril must be adjusted according to the patient's creatinine clearance (see section 4.2), and then as a function of the patient's response to treatment. The dose should not exceed that necessary for adequate control and should be reduced in patients with impaired renal function.
Evaluation of the patient should include assessment of renal function (monitoring of potassium and creatinine) prior to initiation of therapy and at appropriate intervals thereafter. Patients with renal impairment should not normally be treated with captopril.
Aortic and mitral valve stenosis/ Obstructive hypertropic cardiomyopathy: Captopril should be used with caution in patients with left ventricular valvular and outflow tract obstruction. As limited experience has been obtained in the treatment of acute hypertensive crises, the use of captopril should be avoided in cases of cardiogenic shock and haemodynamically significant obstruction.
Angioedema: angioedema of the extremities, face, lips, mucous membranes, tongue, glottis or larynx may occur in patients treated with ACE inhibitors including Captopril. This may occur anytime during treatment. However, in rare cases, severe angioedema may develop after long- term treatment with an ACE inhibitor. In such cases, Captopril should be discontinued promptly and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. In those instances where swelling has been confined to the face and lips the condition generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema involving the tongue, glottis or larynx may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, which may include subcutaneous epinephrine solution 1:1000 (0.3 ml to 0.5 ml) and/or measures to ensure a patent airway, should be administered promptly. The patient should be hospitalised and observed for at least 12 to 24 hours and should not be discharged until complete resolution of symptoms has occurred.
Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-blacks.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see section 4.3).
Intestinal angioedema has also been reported rarely in patients treated with ACE inhibitors.
These patients presented with abdominal pain (with or without nausea or vomiting); in some cases, there was no prior facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan, or ultrasound or at surgery and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain (see section 4.8).
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to the increased risk of angioedema. Treatment with sacubitril/valsartan must not be initiated earlier than 36 hours after the last dose of captopril. Treatment with captopril must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections 4.3 and 4.5).
Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin may lead to an increased risk of angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (see section 4.5). Caution should be used when starting racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin in a patient already taking an ACE inhibitor.

Cough: cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non-productive, persistent and resolves after discontinuation of therapy.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE- inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).
If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.
ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Hepatic failure: rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.
Hyperkalaemia:
ACE inhibitors can cause hyperkalemia because they inhibit the release of aldosterone. The effect is usually not significant in patients with normal renal function. However, in patients with impaired renal function and/or in patients taking potassium supplements (including salt substitutes), potassium-sparing diuretics, trimethoprim or cotrimoxazole also known as trimethoprim/sulfamethoxazole and especially aldosterone antagonists or angiotensin receptor blockers, hyperkalemia can occur. Potassium sparing diuretics and angiotensin receptor blockers should be used with caution in patients receiving ACE inhibitors, and serum potassium and renal function should be monitored (see section 4.5). Patients at risk for the development of hyperkalaemia include those with renal insufficiency, diabetes mellitus, or those using concomitant potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes; or those patients taking other drugs associated with increases in serum potassium (e.g. heparin). If concomitant use of the above mentioned agents is deemed appropriate, regular monitoring of serum potassium is recommended.
Lithium: the combination of lithium and captopril is not recommended (see section 4.5) Proteinuria: Proteinuria may occur particularly in patients with existing renal function impairment or on relatively high doses of ACE inhibitors.
Total urinary proteins greater than 1 g per day were seen in about 0.7% of patients receiving captopril. The majority of patients had evidence of prior renal disease or had received relatively high doses of captopril (in excess of 150 mg/day), or both. Nephrotic syndrome occurred in about one-fifth of proteinuric patients. In most cases, proteinuria subsided or cleared within six months whether or not captopril was continued. Parameters of renal function, such as BUN and creatinine, were seldom altered in the patients with proteinuria.
In patients with evidence of prior renal disease should have urinary protein estimations (dip stick on first morning urine) prior to treatment, and periodically thereafter.
Although membranous glomerulopathy was found in biopsies taken from some proteinuric patients, a causal relationship to captopril has not been established.
Anaphylactoid reactions during desensitisation: There have been rare reports of sustained life-threatening anaphylactoid reactions in patients undergoing desensitisation treatment with hymenoptera venom while receiving another ACE inhibitors. In the same patients, these reactions were avoided when the ACE inhibitor was temporarily withheld, but they reappeared upon inadvertent rechallenge. Therefore caution should be used in patients treated with ACE inhibitors undergoing such desensitisation procedures.
Anaphylactoid reactions during high-flux dialysis / lipoprotein apheresis membrane exposure: Recent clinical observations have shown a high incidence of anaphylactoid-like reactions during haemodialysis with high-flux dialysis membranes (e.g. AW 69) or undergoing low-density lipoprotein apheresis with dextran sulphate absorption in patients receiving ACE inhibitors. Therefore, this combination should be avoided. In these patients, consideration should be given to use a different type of dialysis, membrane or a different class of medication.
Diabetic patients: the glycaemia levels should be closely monitored in diabetic patients previously treated with oral antidiabetic drugs or insulin, namely during the first month of treatment with an ACE inhibitor.
Renal function in patients with Heart failure: Some patients may develop stable elevations of BUN and serum creatinine >20% above normal or baseline upon long-term treatment with captopril. A few patients, generally those with severe pre-existing renal disease, required discontinuation of treatment due to progressively increasing creatinine.
Neutropenia/Agranulocytosis: neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE inhibitors, including captopril. In patients with normal renal function and no other complicating factors, neutropenia occurs rarely.
Captopril should be used with extreme caution in patients with pre-existing impaired renal function, collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors. Some of these patients developed serious infections which in a few instances did not respond to intensive antibiotic therapy.
If captopril is used in such patients, it is advised that white blood cell count and differential counts should be performed prior to therapy, every two weeks during the first three months of captopril therapy, and periodically thereafter.
During treatment all patients should be instructed to report any sign of infection (e.g. sore throat, fever), when a differential white blood cell count should be performed. Captopril and other concomitant medication (see section 4.5) should be withdrawn if neutropenia (neutrophils less than 1000/mm3) is detected or suspected.
In most patients neutrophil counts rapidly returned to normal upon discontinuing captopril.
Surgery/Anaesthesia: In patients undergoing major surgery, or during anaesthesia with agents which produce hypotension, captopril will block angiotensin II formation secondary to compensatory renin release. This may lead to hypotension which can be corrected by volume expansion.
Lactose: Aceril contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Ethnic differences: As with other angiotensin converting enzyme inhibitors, captopril is apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of a higher prevalence of low-renin states in the black hypertensive population.
Pregnancy: ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started. (See sections 4.3 and 4.6).

Effects on Driving

4.7 Effects on ability to drive and use machines

As with other antihypertensives, the ability to drive and use machines may be reduced, namely at the start of the treatment, or when posology is modified, and also when used in combination with alcohol, but these effects depend on the individual's susceptibility.